HUT61463A - Process for producing locally applicable antifungal compositions with antiinflammatory activity, comprising imidazole derivatives - Google Patents

Abstract

The certain imidazoles have been found to exhibit anti-inflammatory as well as antifungal activity.

Description

A class of imidazole derivatives is known for its antifungal activity. Thus, Tannenbaum L. et al., 2 Arch. Dermatol. 120, 216-219 / 1984 // The effect of sulconazole and miconazole cream on Tinea Versicolor is described. Qadripur S.A./Current Ther. Gap. 55, 755-758 / 1984, found that 1% Sulkonazole Cream, in combination with Sulkonazole Powder, can be used to treat skin dermatophytosis with about the same results as 1% Econazole Cream and Powder.

Of the imidazole derivatives, compounds of formula (I) wherein

X is oxygen or sulfur and n = 1, 2 or 5, or pharmaceutically acceptable derivatives thereof, such as their nitrate salts, are particularly preferred for anti-combative treatment.

Comparative study of sulconazole nitrate cream and clotrimazole cream in the treatment of dermatophytosis showed faster systemic improvement in the sulconazole treated group / Lassus A., Brit. J. Dermatol. 108, 195-198 / 1985 //.

In the treatment of skin candidiasis, the efficacy of sulconazole nitrate cream was superior to both vehicle and miconazole nitrate cream / Tannenbaum L. et al., Internat. J. Dermatol. 22, 518-520 / 1985 //.

In the treatment of dermatophytosis, sulconazole provided faster and more complete relief to patients compared to econazole (A. Lassus et al., Mykosen 2: 594-598 / 1984).

Combining imidazoles with steroids is a well-known method of treating fungal infections. Steroids are believed to work in the first days of treatment, reducing inflammation, while imidazoles work for several weeks, usually 5-5 weeks, while fungi are eliminated.

British Patent No. 1474510, filed May 25, 1977, describes ointments containing imidazoles (antifungal agents) and steroids (anti-inflammatory agents). Similarly, U.S. Patent 4,298,604 discloses an antifungal composition comprising clotrimazole and betamethasone dipropionate.

U.S. Patent No. 5,002,958 describes a topical antifungal gel containing imidazoles and 17-ester corticosteroids for the treatment of fungal infections.

Interestingly, the usefulness of the baby moles themselves in the treatment of inflammation has not been directly investigated so far. However, immunological effects of some imidazole derivatives have been reported.

Erouket E. et al. / Zentralblatt für Bakteriologie, Farasitenkunde, Infektionskrankheiten

- 4 und Hygiene, Suppl, 13, 1-37 / 1985 - ketoconazole is described as an immunomodulator with a dose-dependent effect. Miconazole has been shown to be immunosuppressive against late-type hypersensitivity reactions, so it can be used to prevent transplant rejection.

Watanabe, K., et al. / Fharmacometrics / Japan / 29, 501-515 / 19'85 / 7, also describe the immune response, phototoxic and photoallergenic responses of guinea pigs to sulconazole in various forms.

The enzymes 5-lipoxygenase and cyclooxygenase catalyze the formation of leukotrienes, an important media of inflammation. Steinhilber, D., et al. / Arzneim.-Forsch./Lrug Slit. 40, 1260-1265 / 199θ / 7, itraconazole inhibits 5-lipoxygenase in cell culture in vitro but does not inhibit cyclooxygenase. However, none of the other azoles tested, such as fluconazole, ketoconazole and miconazole, showed significant activity in this model.

The above literature data are incorporated herein by reference.

Some imidazoles and their pharmaceutically acceptable salts have been found to have anti-inflammatory activity during the first week of topical application. These effects are in addition to the well-known antifungal activity of imidazoles.

Thus, the compounds and methods of the invention need only be applied for about 2-7 days, preferably about 3-5 days, to produce anti-inflammatory effects.

According to a preferred embodiment, "Sulkonazole gel prepared with SD alcohol-containing carrier on a 6-week skin surface / athlete's foot", within 1 to 1 day

It is accompanied by a decrease in it so within one week the itching, burning / tingling sensation and pain / tenderness are almost eliminated or suggest that sulconazole is as effective as an anti-inflammatory agent as hyrocortisone valerate / HCV /

HCV is a moderately effective steroid used in my clinic to treat inflammatory conditions of the skin.

The present invention further relates to the treatment of substances and inflammation, such as the elimination of fungi

A further object is to provide a carrier which is an inflammatory and / or fungal condition

The compositions and methods of the present invention have several advantages over other systems for treating inflammatory and fungal conditions.

Because there is no need to add antiinflammatory agent (s), the systems of the invention are less expensive, for example, in steroid / imidazole or antimicrobial agent / imidazole combinations. In addition, non-steroid systems do not cause steroid therapeutic side effects such as skin atrophy.

In addition, compatibility which is often associated with the use of formulations containing two or more active ingredients can be avoided! problems. For example, special mixing procedures are often used to ensure proper distribution of the active ingredient (s).

Finally, there are no stability problems commonly encountered with steroid combinations.

These and other objects and advantages will become apparent from the following description and the claims.

Unless otherwise indicated, the percentages given are by weight relative to the total weight of the composition.

The compounds useful in the compositions of the invention are generally of formula (I) wherein

X is O or S and n = 1, 2 or 3 and pharmaceutically acceptable derivatives thereof.

Preference is given to compounds wherein

X represents sulfur and n = 1, such as sulconazole; and compounds wherein

X represents an oxygen atom and η = 1 or 2, i.e. econazole and miconazole. Most preferred is sulco nazole.

Under pharmaceutically acceptable derivatives, it is used as antiinflammatory and antifungal agents

- We refer to basic or acid addition salts having 8 lenticidal activity. Nitrates are most preferred.

Sulcononazole nitrate is most preferred.

Mixtures of compounds may also be used.

One or more of the above compounds may be applied topically to the skin and / or hair of the patient following the formulations of the present invention, and are formulated as creams, gels, ointments, solutions, powders, pastes and the like. Preference is given to creams and gel formulations, most preferably gels. One or more dosage forms may be used concurrently during treatment, for example creams and powders may be used together.

The compositions of the invention need not contain any active ingredient other than one or more of the compounds of formula (I) above. However, these formulations will generally contain an appropriate amount of a pharmaceutically acceptable excipient to improve flow properties, commercial appearance, packaging and / or handling properties. such as perfumes, dyes, fillers, curls, surfactants, moisturizers, softeners, gelling agents, carriers,

- 9 preservatives, stabilizers and the like can be used.

If a gel composition is desired, preferred additives include gelling agents (e.g., hydroxyalkylcelluloses, such as hydroxypropylcellulose), solvents (e.g., monovalent alcohols, divalent and trivalent alcohols), plasticizers (e.g., propylene glycol, isopropyl myristate). and preservatives such as butylhydroxytoluene, BHT; of salicylic acid.

When a cream is needed, adjuvants such as emulsifiers (e.g. sorbitan esters, polysorbates), water, plasticizers (e.g. isopropyl myristate, propylene glycol), waxes (e.g. stearyl alcohol, cetyl alcohol) and preservatives (e.g. BHT, ascorbyl) are often required. palmitate / can be used.

Liquid formulations may be sprayed with a large amount of one or more carriers, such as propylene glycol, water, alcohol / alcohol and the like.

Powder formulations include fillers such as talc, starch, magnesium stearate and the like, and coloring agents such as ED + C Red No. 4 and ED + C Yellow No. 5 and the like.

In addition, one or more substances for stabilizing the composition may be used. thus, sufficient amounts of antioxidants such as BHT, ascorbyl palmitate, rheological stabilizers as cellulose derivatives,

- 10 carbopol and the like can be used. Suitable amounts of the agents and excipients to be used according to the invention are shown in the following table.

Mixtures of the above additives may also be used.

additive Wide range Preferred range Most preferred range As / s / 0.01-10% 0 0.2-2.0% Binder / s / 0.01 to 99.9% 5 to 99.9% 5 to 99.8% Stabilizing / k / 0.01 to 99.9% 0.01-10% 0.01-10% The invention individual. advantageous

The composition of the items may be as follows:

Imidazole antifungal agent 0.2-2.0% ”SD alcohol 40”. 30-65%

1,2,6-hexanetriol 0-45%

2-ethyl-1,3-hexanediol 0-40%

Isopropyl myristate 0-40%

PFG-20 Methyl Glucose Ether 0-10%

Hydroxypropylcellulose 0.1-5%

Salicylic acid 0.1-5%

BHT 0.01-2%

In NaOH solution as needed to reach pH 4.0.

The methods of the invention include the treatment of fungal infections and other conditions associated with inflammatory skin symptoms. Conditions to be treated according to the present invention include tinea pedis, tinea cruris / foot, leg fungal infection, tinea capitis / ringworm, skin candidiasis and the like.

In treating the above and other conditions associated with inflammatory and / or fungal manifestations, the patient's hair and / or skin is contacted with one or more compositions containing the active ingredient. thus, the agent is applied topically to the host rather than orally or parenterally. '

Although gels, creams and ointments are the preferred formulations for stability, they may not be medically suitable. Therefore, spraying, dusting, brushing, and the like may be used to contact the host hair or epidermis with the active ingredients.

"Epidermis" refers to both hairy scalp and non-hairy tissue.

The term "host" may refer to any mammal. Although preferred to humans, the compositions of the invention may also be used to treat dogs, cats and other furry mammals.

• ·

Generally, any host surface area of the host can be treated in accordance with the present invention. Nasal or ophthalmic application is also contemplated, but is not preferred.

It should be emphasized that the wishes and common sense of the physician experienced in treating the patient may modify the treatment regimes suggested below.

The compositions of the invention are applied topically using sufficient amounts to cover the affected skin. Usually 2-3 times a day, but once a day may be sufficient.

Preference is given to cream gel formulations applied 2-3 times daily for about 28-42 days (i.e. 4-6 weeks). Powders and sprays can be used at the same time.

The following examples illustrate the invention.

Example 1

component

Sulconazole nitrate

SD Alcohol 40

1,2,6-Hexántrio1

2-ethyl-5-hexanediol

Isopropyl myristate

PPG-20 methyl glucose ether

Hydroxypropyl cellulose

salicylic Acid

Butylhydroxytoluene / BHT /

Quantity, weight%

1.00

52.40

27.00

7.50

7.50

5.00

0.90

0.50

0.20

In NaOH solution as needed to pH 4.0

Example 2

component Quantity, weight% Econazole nitrate 1.00 SD Alcohol 40 52.40 1,2,6hexanetriol 27.00 2-ethyl-5-hexanediol 7.50 taste opropi1-myristate 7.50 PPG-20 methyl glucose ether 5.00 Hydroxypropyl cellulose 0.90 salicylic Acid 0.50 BHT 0.50 In NaOH solution required to pH 4.0

component Quantity, wt% clotrimazole 1.00 SD Alcohol 40 52.40 1,2,6hexanetriol 27, GO 2-Eti1-1,5 hexándiο1 7.50 Isopropyl myristate 7.50 PPS-20 methyl glucose ether 3.00 Hydroxypropyl cellulose 0.90 salicylic Acid 0.50 BHT 0.20 In NaOH solution required according to pH 4.0- • Ig Example 4 component Quantity, crowd% Sulconazole nitrate 1.00 SD Alcohol 40 50.20 Fropilénglikol 33,00 Isopropyl myristate 5.00 Water 5.00 PPG- 5- c e t e th-2 0 4.20 Hydroxypropyl cellulose 0.90 salicylic Acid 0.50 Ascorbyl palmitate 0.20 In NaOH solution required according to pH 4.0- • up

(»* · •« · • ·· *

- 15 5 «Example

component Quantity, crowd% Sulconazole nitrate 1.00 SD Alcohol 40 35.00 propylene 40.00 PPG-5-ceteth-20 12.45 Isopropyl myristate 5.00 Hydroxypropyl cellulose 0.90 salicylic Acid 0.50 Ascorbyl palmitate 0.10 In NaOH solution as needed pH 4.0 Example 6 component Quantity, wt% Sulconazole nitrate 1.00 Water 53.70 propylene 25.00 Isopropyl myristate 6.00 Cetyl alcohol 3.00 Polysorbate 60 2.00 Sorbitan monostearate 1.00 Glyceryl monostearate SE 0.30 Ascorbyl palmitate 0.02 In HaOH solution as needed pH 4.0

• " ··· " · · * · " ""·"·" · • ··· ·· ·" the · ·

Example 7 component Quantity, weight% Sulconazol nitrate 1.00 propylene 55.00 Poloxamer 407 12.00 Polysorbate 20 4.00 Butylated hydroxyanisole /BHA./ 0.01 Water need s zerin to 100 ml In NaOH solution as required pH 4.5 to 5.5.

One skilled in the art will recognize that reasonable modifications can be made without departing from the spirit and scope of the invention.

Claims (8)

Claims CLAIMS 1. A composition for the topical treatment of dermatitis consisting essentially of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein X is oxygen or sulfur and n = 1, 2 or J and / b / a pharmaceutically acceptable carrier. Composition according to claim 1, characterized in that sulphonazole, econazole or miconazole or a mixture thereof are used as component (a). 3. The composition of claim 1 wherein the amount of component / a is from about 0.2 to about 2% by weight. 4. The composition of claim 1, wherein the component (a) is sulconazole. 5. A carrier for a composition suitable for treating a fungal or inflammatory condition of the skin, comprising essentially the following ingredients: ···· * · ···: χ · ** · χ ·· * · · · · ···· · 9 · «· ·· - 18 / & / a lower alcohol / b / a trivalent alcohol / c / a divalent alcohol / d / water / e / plasticizer / k / / f / a gelling agent / g / preservative (s). The carrier of claim 5, which comprises from about 0% to about 65% w / w component / component, from about 0% to about 4% w / w component / b / component, from about 0% to about 40% w / w component / component and % / d / component, about 0-50% w / w component, about 0.1-5% w / w component and about 0-5% w / w component. 7. A method of treating an inflammatory condition of the skin or scalp, comprising contacting the area to be treated with a composition consisting essentially of at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein X is O or S and n = 1,2 or 5; and / b / a pharmaceutically acceptable carrier. 44 4 ··· 4 · · 4 · · · · ··· · · 4 · 4 · · · · The process of claim 7, wherein the composition is in the form of a gel.